This invention relates to methods and compositions for treatment or prophylaxis of tissue damage, particularly tissue damage incident to hypoxia.
Tissue damage can result when oxygen supply is insufficient to meet metabolic demands. This problem is clinically significant in that morbidity and mortality often result from tissue hypoxia, i.e., a drop in the partial pressure of oxygen to a given tissue below a level at which the cells are able to perform their normal functions aerobically. Under these conditions, the cells die or are forced to switch to alternate metabolism (e.g., glycolysis). Hypoxia can be caused by various medical conditions, including atherosclerosis, chronic illness, trauma, and even surgical procedures. Individuals affected include patients with atherosclerotic heart disease, peripheral vascular disease, cerebral vascular disease and those with problems of wound healing.
The physiological response to hypoxia has been studied at the level of organ systems and cells. Adaptive responses include increased respiratory rate, changes in vascular tone, the stimulation of red blood cell formation and new blood vessel formation (angiogenesis). These adaptations enhance cellular survival during periods of low oxygen availability. Less is known about the molecular mechanisms inducing the response, although the expression of certain genes is regulated following periods of hypoxic shock, including genes encoding: erythropoietin (Beru et al., 1986; Boundourant and Koury, 1986), platelet-derived growth factor B chain (Kourembanas et al., 1990), endothelin (Kourembanas et al., 1991), interleukin-1.alpha. (Shreeniwas et al., 1990) ornithine decarboxylase (Longo et al., 1993), and vascular endothelial growth factor (Shweiki et al., 1992; Plate et al., 1992). These genes may perform protective and recovery functions in the affected tissue.
The vascular endothelial growth factor gene (vegF), encoding the protein product known as VEGF or vascular permeability factor, is expressed in many tissue types. Various treatments using VEGF have been suggested (e.g., Criscuolo et al., 1989; U.S. Pat. Nos. 5,073,492, 5,194,596, 5,219,739), for ameliorating conditions such as myocardial infarction, diabetic ulcers, and surgical wounds.